Mitochondrial aspartate aminotransferase: a third kynurenate‐producing enzyme in the mammalian brain

@article{Guidetti2007MitochondrialAA,
  title={Mitochondrial aspartate aminotransferase: a third kynurenate‐producing enzyme in the mammalian brain},
  author={Paolo Guidetti and Laura Amori and Michael T. Sapko and Etsuo Okuno and Robert M. Schwarcz},
  journal={Journal of Neurochemistry},
  year={2007},
  volume={102}
}
The tryptophan metabolite kynurenic acid (KYNA), which is produced enzymatically by the irreversible transamination of l‐kynurenine, is an antagonist of α7 nicotinic and NMDA receptors and may thus modulate cholinergic and glutamatergic neurotransmission. Two kynurenine aminotransferases (KAT I and II) are currently considered the major biosynthetic enzymes of KYNA in the brain. In this study, we report the existence of a third enzyme displaying KAT activity in the mammalian brain. The novel… 
Structure, expression, and function of kynurenine aminotransferases in human and rodent brains
TLDR
The biochemical differences of four KATs, specific enzyme activity assays, and the structural insights into the mechanism of catalysis and inhibition of these enzymes are discussed.
Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II.
TLDR
Substrate screening of human KAT II revealed that the enzyme has a very broad substrate specificity, is capable of catalysing the transamination of 16 out of 24 tested amino acids and could utilize all 16 tested alpha-oxo acids as amino-group acceptors.
Thermal stability, pH dependence and inhibition of four murine kynurenine aminotransferases
TLDR
The characteristics reported here could be used to develop specific assay methods for each of the four murine KATs and identify which KAT is affected in mouse models for research and to develop small molecule drugs for prevention and treatment of KAT-involved human diseases.
Human kynurenine aminotransferase II – reactivity with substrates and inhibitors
TLDR
Spectroscopic and functional characterization of both the human wild‐type KATII and a variant carrying the active site mutation Tyr142→Phe and the availability of these assays and spectroscopic analyses demonstrated that (R)‐2‐amino‐ 4‐(4‐(ethylsulfonyl))‐4‐oxobutanoic acid and cysteine sulfinate, reported to be K ATII inhibitors, are poor substrates that undergo slow transamination.
Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives
TLDR
Inhibition assay results and modelling suggests that the 17-sulfate moiety in estradiol disulfate is very important in improving its potency as an inhibitor, increasing the inhibition by approximately 10–100 fold compared to Estradiol.
Biochemical and Structural Properties of Mouse Kynurenine Aminotransferase III
TLDR
It is established that mKAT III is able to efficiently catalyze the transamination of kynurenine to KYNA and has optimum activity at relatively basic conditions of around pH 9.0 and at relatively high temperatures of 50 to 60°C.
Alternative kynurenic acid synthesis routes studied in the rat cerebellum
TLDR
Results suggest that different mechanisms are involved in KYNA production in the rat cerebellum, and that, specifically, DAAO and ROS can function as alternative routes forKYNA production.
Crystal Structure of Human Kynurenine Aminotransferase II*
TLDR
The protein architecture of hKAT-II reveals that it belongs to the fold-type I pyridoxal 5-phosphate (PLP)-dependent enzymes, and it is proposed that hKat-II represents a novel subclass in the Fold- type I enzymes because of the unique folding of its first 65 N-terminal residues.
Pharmacological Manipulation of Kynurenic Acid
TLDR
Low endogenous levels of rat brain KYNA have been found to reduce firing of midbrain dopamine neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brainKYNA levels concomitant with an increased performance in cognitive tests.
...
...

References

SHOWING 1-10 OF 69 REFERENCES
Characterization of rat brain kynurenine aminotransferases I and II
TLDR
A simple methodology for the simultaneous determination of the two KYNA‐producing enzymes in small rat brain tissue samples is described and baseline values for future work in experimentally challenged animals are provided.
Measurement of Rat Brain Kynurenine Aminotransferase at Physiological Kynurenine Concentrations
TLDR
The characteristics of KAT described here are compatible with a central role of the enzyme in brain KYNA function in vivo and should be considered as an etiological factor in pathological phenomena related to dysfunction of excitatory amino acid receptors in the brain.
Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry
TLDR
The antibody revealed discrete, specific staining of KAT II‐positive astrocyte‐like cells throughout the adult rat brain, supporting a neuromodulatory role of KYNA.
Tissue expression and translational control of rat kynurenine aminotransferase/glutamine transaminase K mRNAs.
Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice
TLDR
The results show that gene targeting of mKat-2 in mice leads to early and transitory decreases in brain KAT activity andKYNA levels with commensurate behavioral and neuropathological changes and suggest that compensatory changes or ontogenic expression of another isoform may account for the normalization of KYNA levels in the adult m Kat-2−/− brain.
Perinatal kynurenine pathway metabolism in the normal and asphyctic rat brain
TLDR
The results revealed that the brain and liver content of L-KYN, KYNA and 3-HK is far higher pre-term than postnatally; KAT I and kynurenine 3-hydroxylase activities are quite uniform between E-16 and adulthood, whereas KAT II activity rises sharply after postnatal day 14.
Cloning and Functional Expression of a Soluble Form of Kynurenine/α -Aminoadipate Aminotransferase from Rat Kidney *
TLDR
The isolation of a cDNA clone encoding the soluble form of this aminotransferase isoenzyme from rat (KAT/AadAT) is described and degenerate oligonucleotides were designed from the amino acid sequences of rat kidney KAT/ aadAT tryptic peptides for use as primers for reverse transcription-polymerase chain reaction of rat kidneys RNA.
...
...